Clinical implementation of several of the most promising approaches to the treatment of type 1 diabetes will require the ability to perform genetic modifications of specific target cells in human patients in vivo. The pancreatic beta-cell is the most important target and therapeutic opportunities include the induction of regeneration, suppression of autoimmunity and upregulation of anti-oxidant pathways. Several other cell types have potential to be reprogrammed to functional beta-cells by directed fate conversion using transcription factors and microRNAs. This list includes pancreatic acinar cells, biliary duct epithelium of the liver, gall bladder epithelium, pancreatic delta-cells and alpha-cells. The goal f this application is to develop recombinant adeno-associated virus (rAAV) vectors capable of delivering genetic payloads to these target cells in humans efficiently and specifically. rAAV is already being used in several clinical gene therapy applications and has a good safety record. The required precision of gene delivery will be achieved by combining cell-type specific rAAV capsids with gene regulatory elements (promoters, enhancers and microRNA binding sites) that limit expression to only the target cell. rAAV capsid and the regulatory sequences will be optimized for each human cell type using xenograft models.